Bazedoxifene acetate 1-{4-[2-(azepan-1-yl)ethoxy]benzyl}-2-(4-hydroxyphenyl)-3-methyl-1H-indol-5-ol acetate is a third generation selective estrogen receptor modulator. It is used in the prevention and treatment of post menopausal osteoporosis.
Conventional processes for preparing bazedoxifene acetate are disclosed in U.S. Pat. Nos. 5,998,402, 6,380,166, European patent 0802183 and World patent application 2010118997. Miller et al., (J. Med. Chem., 2001, 44, 1654-57) have also described a synthetic preparation of bazedoxifene acetate.
Scheme 1 below summarizes the method disclosed in U.S. Pat. No. 5,998,402, EP 0802183 and in J. Med. Chem. 2001, 44, 1654-57.
Alkylation of the indole of the formula-3 with the compound of formula-4 was accomplished with sodium hydride in N,N-dimethyl formamide. The ester of formula-5 was subsequently reduced with lithium aluminium hydride (LAH) and the primary alcohol of formula-6 thus produced was converted to the corresponding bromide of formula-7 by treatment with carbontetrabromide and triphenylphosphine. Substitution of this bromide of formula-7 with hexamethyleneimine yielded benzylated bazedoxifene of formula-8. Hydrogenation of the compound of formula-8 to bazedoxifene free base of formula-9 was followed by conversion to bazedoxifene acetate of the formula-1.
The drawbacks of this process involve using LAH, a highly flammable and industrially hazardous reagent, and using CBr4 a corrosive and expensive Class 1 solvent and reagent at the bromination stage.

A second method is disclosed in U.S. Pat. No. 6,380,166 and WO 9919293 (Shown as Scheme 2). Alkylation of indole with the compound of formula-10 was accomplished with sodium-tert-butoxide in N,N-dimethyl formamide yielding benzylated bazedoxifene directly. The remaining steps are similar to the Scheme I above.

The WO 2011022596A2 application discloses a process similar to the one described in U.S. Pat. No. 6,380,166, wherein the alkylation of indole with the compound of formula-10 was prepared by using sodium hydride in DMF to yield the benzylated bazedoxifene of formula-8 along with C-alkylated impurity of formula-23. This impurity subsequently undergoes reaction to give debenzylated impurity of formula-22. The impure free base was further converted to bazedoxifene hydrochloride in methanol by treating with aqueous hydrochloric acid. However, the described process resulted in a yield loss of 20 to 25%.

World Patent application 2010118997 discloses a third route of synthesis. (Shown in Scheme 3 below). N-alkylation of indole of formula-3 with 4-chloromethyl phenoxy acetonitrile of formula-11 was effected in the presence of sodamide and N,N-dimethyl formamide to form {4-[5-benzyloxy-2-(4-benzyloxyphenyl)-3-methylindol-1-yl-methyl]phenoxy} of formula-12. Hydrolysis of the nitrile of formula-12 in the presence of sodium hydroxide yielded {4-[5-benzyloxy-2-(4-benzyloxyphenyl)-3-methylindol-1-yl-methyl]phenoxy}acetic acid of formula-13. Reacting this intermediate of formula-13 with 1,1′-carbonyl di-imidazole and the hexamethyleneimine resulted in 1-azepan-1-yl-2-{-4-[5-benzyloxy-2-(4-benzyloxy phenyl)-3-methyl indol-1-yl methyl]phenoxy}ethanone of formula-14. Reducing the compound of formula-14 with NaBH4/BF3 gave benzylated bazedoxifene of the formula-8. Hydrogenation of the compound of formula-8 to bazedoxifene free base of the formula-9 was followed by conversion to bazedoxifene acetate of the formula-1.

These methods result in low yields and reduction of the compound of the formula-14 with NaBH4/BF3 etherate is a critical reaction. Handling of corrosive BF3 etherate on an industrial scale poses a major problem.